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      Overcoming addition of phosphoethanolamine to lipid A mediated colistin resistance in Acinetobacter baumannii clinical isolates with colistin–sulbactam combination therapy

      research-article
      1 , 2 , 1 , 2 , 4 , 8 , 5 , 6 , 7 , 22 , 8 , 22 , 9 , 10 , 22 , 11 , 12 , 13 , 14 , 1 , 2 , 1 , 2 , 3 , 15 , 16 , 22 , 1 , 2 , 22 , 17 , 22 , 18 , 19 , 22 , 20 , 22 , 1 , 21 , 1 , 2 , 22 ,
      Scientific Reports
      Nature Publishing Group UK
      Antimicrobials, Bacteria, Clinical microbiology, Drug discovery, Genetics, Microbiology, Molecular biology, Medical research, Molecular medicine

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          Abstract

          Overcoming colistin-resistant Acinetobacter baumannii (CoR-AB) has become a major concern due to the lack of effective antibiotics. This study aimed to explore the prevalence of CoR-AB clinical isolates in Thailand, their mechanisms of resistance, and test the efficacy of colistin plus sulbactam against CoR-AB isolates. The colistin resistance rate among carbapenem-resistant A. baumannii was 15.14%. The mcr gene or its variants were not detected in CoR-AB isolates by PCR screening. The lipid A mass spectra of CoR-AB isolates showed the additional [M–H] ion peak at m/ z = 2034 that correlated to the phosphoethanolamine (pEtN) addition to lipid A (N = 27/30). The important amino acid substitutions were found at position S14P, A138T, A227V in PmrB that are associated with overexpression of the pEtN transferase (PmrC) and contributed the pEtN addition. The lipopolysacccharide production genes ( lpxACD) were not related to lipid A mass spectra. A colistin plus sulbactam combination exhibited the synergy rate at 86.7% against CoR-AB isolates compare to sulbactam (85.89% resistance) or colistin (15.14% resistance) alone. The excellent synergistic activity of colistin plus sulbactam combination has the potential for the treatment of CoR-AB infections.

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          Most cited references41

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          Identification of a novel transposon-associated phosphoethanolamine transferase gene, mcr-5, conferring colistin resistance in d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B.

          Plasmid-mediated mobilized colistin resistance is currently known to be caused by phosphoethanolamine transferases termed MCR-1, MCR-2, MCR-3 and MCR-4. However, this study focuses on the dissection of a novel resistance mechanism in mcr-1-, mcr-2- and mcr-3-negative d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B (Salmonella Paratyphi B dTa+) isolates with colistin MIC values >2 mg/L.
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            Colistin resistance of Acinetobacter baumannii: clinical reports, mechanisms and antimicrobial strategies.

            Colistin is the last resort for treatment of multidrug-resistant Acinetobacter baumannii. Unfortunately, resistance to colistin has been reported all over the world. The highest resistance rate was reported in Asia, followed by Europe. The heteroresistance rate of A. baumannii to colistin is generally higher than the resistance rate. The mechanism of resistance might be loss of lipopolysaccharide or/and the PmrAB two-component system. Pharmacokinetic/pharmacodynamic studies revealed that colistin monotherapy is unable to prevent resistance, and combination therapy might be the best antimicrobial strategy against colistin-resistant A. baumannii. Colistin/rifampicin and colistin/carbapenem are the most studied combinations that showed promising results in vitro, in vivo and in the clinic. New peptides showing good activity against colistin-resistant A. baumannii are also being investigated.
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              Resistance to polymyxins in Gram-negative organisms.

              Polymyxins have recently been re-introduced into the therapeutic arsenal to combat infections caused by multidrug-resistant Gram-negative bacteria. However, the emergence of strains resistant to these last-resort drugs is becoming a critical issue in a growing number of countries. Both intrinsic and transferable mechanisms of polymyxin resistance have been characterised. These mechanisms as well as the epidemiological data regarding four relevant bacterial pathogens (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa) are considered in this review. A special focus is made on plasmid-mediated resistance and the spread of mcr genes.
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                Author and article information

                Contributors
                Tanittha.C@chula.ac.th
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                6 July 2022
                6 July 2022
                2022
                : 12
                : 11390
                Affiliations
                [1 ]GRID grid.419934.2, ISNI 0000 0001 1018 2627, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, , Thai Red Cross Society, ; 1873 Rama 4 Road, Pathum Wan, Bangkok, 10330 Thailand
                [2 ]GRID grid.7922.e, ISNI 0000 0001 0244 7875, Center of Excellence in Antimicrobial Resistance and Stewardship, Faculty of Medicine, , Chulalongkorn University, ; Bangkok, Thailand
                [3 ]GRID grid.7922.e, ISNI 0000 0001 0244 7875, Interdisciplinary Program of Medical Microbiology, Graduate School, , Chulalongkorn University, ; Bangkok, Thailand
                [4 ]GRID grid.1012.2, ISNI 0000 0004 1936 7910, School of Medicine, Faculty of Health and Medical Sciences, , The University of Western Australia, ; Nedlands, WA Australia
                [5 ]GRID grid.6190.e, ISNI 0000 0000 8580 3777, Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital Cologne, , University of Cologne, ; Cologne, Germany
                [6 ]GRID grid.452463.2, German Centre for Infection Research, , Partner Site Bonn-Cologne, ; Cologne, Germany
                [7 ]GRID grid.1049.c, ISNI 0000 0001 2294 1395, Statistics, , QIMR Berghofer Medical Research Institute, ; Brisbane, QLD Australia
                [8 ]GRID grid.417323.0, ISNI 0000 0004 1773 9434, Department of Infectious Diseases and Infection Control, , Yamagata Prefectural Central Hospital, ; Yamagata, Japan
                [9 ]GRID grid.411554.0, ISNI 0000 0001 0180 5757, Department of Brain and Neurology, , Mae Fah Luang University Hospital, ; Chiang Rai, Thailand
                [10 ]GRID grid.411554.0, ISNI 0000 0001 0180 5757, School of Integrative Medicine, , Mae Fah Luang University, ; Chiang Rai, Thailand
                [11 ]GRID grid.9723.f, ISNI 0000 0001 0944 049X, Department of Computer Science, Faculty of Science, , Kasetsart University, ; Bangkok, Thailand
                [12 ]GRID grid.10223.32, ISNI 0000 0004 1937 0490, Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, , Mahidol University, ; Bangkok, Thailand
                [13 ]GRID grid.7922.e, ISNI 0000 0001 0244 7875, Department of Physiology, Faculty of Medicine, , Chulalongkorn University, ; Bangkok, Thailand
                [14 ]GRID grid.7922.e, ISNI 0000 0001 0244 7875, Center of Excellence for Microcirculation, Faculty of Medicine, , Chulalongkorn University, ; Bangkok, Thailand
                [15 ]GRID grid.490170.b, Department of General Surgery, , Fuling Center Hospital of Chongqing City, ; Chongqing, China
                [16 ]GRID grid.412434.4, ISNI 0000 0004 1937 1127, Chulabhorn International College of Medicine, , Thammasat University, ; Bangkok, Thailand
                [17 ]GRID grid.7914.b, ISNI 0000 0004 1936 7443, Department of Clinical Science, , University of Bergen, ; Bergen, Norway
                [18 ]GRID grid.10223.32, ISNI 0000 0004 1937 0490, Department of Emergency Medicine, Center of Excellence, Faculty of Medicine Ramathibodi Hospital, , Mahidol University, ; Bangkok, Thailand
                [19 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Institute of Clinical Sciences, Department of Surgery, Sahlgrenska Academy, , Gothenburg University, ; 40530 Gothenburg, Sweden
                [20 ]School of Pharmacy & Technology Management,, SVKM’s Narsee Monjee Institute of Management Studies (NMIMS), Hyderabad, 509301 India
                [21 ]GRID grid.7922.e, ISNI 0000 0001 0244 7875, Translational Research in Inflammation and Immunology Research Unit (TRIRU), Department of Microbiology, , Chulalongkorn University, ; Bangkok, Thailand
                [22 ]GRID grid.417323.0, ISNI 0000 0004 1773 9434, Pathogen Hunter’s Research Collaborative Team, Department of Infectious Diseases and Infection Control, , Yamagata Prefectural Central Hospital, ; Yamagta, Japan
                Article
                15386
                10.1038/s41598-022-15386-1
                9259700
                35794134
                7ff95d3e-dd2d-47e1-b959-9e4b9229e0ae
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 28 November 2021
                : 23 June 2022
                Funding
                Funded by: H.M. The king Bhumibhol Adulyadej’s 72nd birthday anniversary scholarship
                Funded by: 90th Year Anniversary scholarship Chulalongkorn University
                Funded by: 90th Year Anniversary Ratchadapiseksompotch Endowment Fund
                Funded by: Chulalongkorn University (Second Century Fund- C2F Fellowship)
                Funded by: Overseas Research Experience Fellowship
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                © The Author(s) 2022

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                antimicrobials,bacteria,clinical microbiology,drug discovery,genetics,microbiology,molecular biology,medical research,molecular medicine

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